Posttraumatic stress disorder (PTSD) is a disabling chronic psychiatric disorder that affects more than 8% of the population. New treatments for PTSD symptoms are desperately needed because current pharmacologic and behavioral treatments for PTSD are inadequate or they have low uptake. Accumulating evidence supports elevated inflammation as a new potential treatment target for PTSD. Inflammation is increased in PTSD, and can promote threat sensitivity, a core mechanism underlying several PTSD symptoms including hyperarousal, anxiety, sleep disturbance, and anger. Two major gaps in knowledge prevent progress towards effective anti- inflammatory treatments for PTSD symptoms. First, we know little about the relationship between chronic inflammation and exaggerated threat sensitivity. Second, no studies have directly examined the effects of acute inflammation on neural and behavioral measures of threat sensitivity in PTSD. The training objective of this K01 Career Development Award proposal is to allow the applicant to acquire expertise in neuroscience and neuroimaging, psychoneuroimmunology, and clinical stress and PTSD research from a world-leading mentoring team that will facilitate her research on the psychoneuroimmunology of PTSD. The research objective of this proposal is to uncover the effects of chronic and acute inflammation on neural mechanisms and behavioral measures of threat sensitivity in individuals with and without PTSD symptoms. The central hypothesis is that both chronic and acute inflammation will be associated with exaggerated threat sensitivity overall, with particularly strong relationships in PTSD. The scientific rationale is that establishng a link between elevated inflammation and threat sensitivity in both observational and experimental studies in individuals with and without PTSD symptoms will drive progress towards a targeted approach to identifying effective anti- inflammatory treatments for PTSD symptoms. In particular, this work has the potential to identify a target for clinical trials of anti-inflammtory interventions in PTSD. Guided by preliminary data, hypotheses will be tested by pursuing two specific aims: 1) Examine the association of chronic inflammation with threat sensitivity; and 2) Determine the effects of an acute inflammatory challenge on threat sensitivity. To achieve these aims, 40 male military veterans with moderate to severe PTSD symptoms and 40 age- and body mass index-matched trauma-exposed male veterans with no history of PTSD will be recruited from an ongoing study (N=746 Veterans Affairs patients). We will assess chronic resting levels of inflammation (Aim 1) and will randomize participants to placebo or inflammatory challenge using polysaccharide typhoid vaccine (i.e., endotoxin) (Aim 2) and will use validated functional MRI paradigms and behavioral tasks to assess threat sensitivity. This proposal and training plan are in line with the goals of the NIMH Strategic Plan and the Research Domain Criteria project, will provide new insights into the inflammation-threat sensitivity relationship in PTSD, and will fll key training gaps to allow the applicant to pursue critical follow-up projects as an independent investigator.